This project focuses on the mechanisms involved in the neural control of metabolism and gene expression and uses the pineal gland as a neural model to study these questions. Major new discoveries in the project are: (1) Both cyclic AMP and cyclic GMP are regulated by the synergistic action of two receptors for norepinephrine, an alpha1-adrenoceptor and a beta1-adrenoceptor. This discovery is of profound importance, because it is an exception to the general belief that these receptors always oppose each other. (2) Alpha1-adrenoceptors appear to regulate cyclic AMP through a fatty acid second messenger cascade system, involving phosphatidylinositol turnover, production of diacylglycerol, stimulation of protein kinase c, and sensitization of adenylate cyclase to beta1-adrenoceptor stimulation. (3) It was found that tonic neural stimulation of the pineal gland is required for the stimulation of one enzyme, hydroxyindole-O-methyltransferase, whereas the activity of another enzyme involved in melatonin synthesis, N-acetyltransferase, responds immediately to neural stimulation. This is important because it provides investigators with a model to study how neural signals control both rapid and gradual changes in the activities of specific enzymes. (4) N-acetyltransferase in the pineal gland, in sharp contrast to other tissues, is actually two enzymes, arylakylamine N-acetyltransferase and arylamine N-acetyltransferase. Only the former is neurally regulated and can acetylate serotonin. These two enzymes, which may represent the product of either one or two genes, were characterized. (5) It has been possible to purify hydroxyindole-O-methyltransferase rapidly, using a novel affinity column. This will make future studies more efficient for workers in this area.